Design,Synthesis And Biological Evaluation Of The New ALK Kinase Inhibitors And Rhodium(Ⅲ)-Catalyzed C-H Activation

The global incidence of lung cancer is still one of the highest cancer mortality rate;new cases of lung cancer are more than 1.5 million each year.Moreover,there are more than 100 million deaths and trend have been rising every year.There are two types of lung cancer:small cell lung cancer and non-small cell lung cancer(NSCLC)which accounted for 85%.ALK mutation is closely related to the pathogenesis of several human cancer,especially non-small cell lung cancer.As the insulin receptor family,anaplastic lymphoma kinase(ALK)is a class of transmembrane receptor tyrosine kinase which was originally found in anaplastic large cell lymphoma(ALCL)patients.Cytotoxic chemotherapy was thought to be the primary treatment means of metastatic non-small cell lung cancer(NSCLC).However,this "One Fits All" has reached a common way of treating bottlenecks,and gradually being replaced by individualized treatment methods,such as molecular targeted therapy,which indicates that the non-small cell lung cancer individualized treatment of new era is coming.Based on advanced targeted therapies,Crizotinib was considered to be standardization program to rearranged ALK patients with advanced non-small cell lung cancer.Unfortunately,most patients in response to 12 months after the beginning,produce resistance.Thus,research for the next generation ALK kinase inhibitor is imminent.The first chapter of this article reviews the ALK gene and discovery process of gene mutation,and milestone discovery of Crizotinib brought hope to non-small cell lung cancer patients,but with the emergence of resistance,we need to study more promising next-generation drug with higher activity and better targeting ALK kinase inhibitor drugs.The second chapter,based on the results of our virtual screening,a new class structure of ALK kinase inhibitors of pyrazolopyridine class parent nucleus was developed,after the completion of more than a dozen chemical synthesis of compounds,activity screening were carried out.We found two compounds of nice activity A8 and A10,IC50 can reach nearly 40 nM.Meanwhile,in the third chapter,we first review progress of the metals rhodium(Ⅲ)-catalyzed C-H activation.Then we carried out a related study effectively.Respectively,we used triazene and salicylaldehyde as starting materials,then we got a number of useful derivative compound simplely and efficiently,meanwhile this method was applied to the synthesis of heterocyclic compounds.